EPS8L2 (EPS8-like protein 2) is a cytoplasmic actin-regulatory adaptor of the EPS8 family, built from an N-terminal PTB-like domain, a central SH3 domain and a C-terminal effector region that binds F-actin and SOS1. In fibroblasts, EPS8L2 binds ABI1 and assembles with ABI1 and the dual Ras/Rac exchange factor SOS1 into a complex with Rac-GEF activity, binds actin filaments directly, is recruited to growth-factor-induced membrane ruffles, and can substitute for EPS8 in driving receptor tyrosine kinase-induced Rac-dependent ruffling; EPS8 and EPS8L2 are broadly co-expressed and functionally redundant in this pathway. In the inner ear, the mouse ortholog localizes to the tips of the shorter rows of hair-cell stereocilia and is required for the long-term maintenance of the hair-bundle staircase and stereocilium width; its loss causes late-onset progressive hearing loss. Biallelic loss-of-function variants in human EPS8L2 cause autosomal recessive progressive non-syndromic hearing loss (DFNB106). EPS8L2 has also been reported to interact with the nuclear envelope phosphatase CTDNEP1 in regulating dorsal actin cables during nuclear positioning in migrating cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003779 actin binding | IBA GO_REF:0000033 | MODIFY | Summary: IBA transfer of actin binding from PAINT node PTN000958212 (donors mouse Eps8, human EPS8L1 and EPS8L2 itself). EPS8L2's own experimental evidence shows direct binding to filamentous actin. Reason: The term is correct but less specific than the evidence. The C-terminal effector region of EPS8L2 co-sediments with polymerized actin, which supports actin filament binding (GO:0051015, is_a actin binding). EPS8L2 appearing in its own WITH/FROM reflects its experimental annotation from PMID:14565974 and is expected, not circular. The node placement is sound for EPS8L2 (EPS8, EPS8L1 and EPS8L2 all bind F-actin; only EPS8L3 does not). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000958212 SUPPORTS TRANSFER Node placement is sound for EPS8L2; the propagated parent term is true but less specific than the direct F-actin co-sedimentation evidence. UniProtKB:Q9H6S3 SUPPORTS TRANSFER EPS8L2's own experimental annotation from PMID:14565974 is among the descendant evidence for this node; expected, not circular. UniProtKB:Q8TE68 SUPPORTS TRANSFER EPS8L1 shares the ABI1/SOS1 Rac-GEF and F-actin-binding properties in the same study. Proposed replacements: actin filament binding Supporting Evidence: PMID:14565974 Consistent with the immunoprecitation results, eps8, eps8L1, and L2, but not eps8L3 could directly associate to F-actin PMID:14565974 Similarly to eps8, eps8L1 and eps8L2, but not eps8L3 coprecipitated with actin |
| GO:0003779 actin binding | IDA PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | MODIFY | Summary: Flag-EPS8L2 co-immunoprecipitates actin from cells, and its purified C-terminal fragment co-sediments with F-actin in vitro (human EPS8L2, PMID:14565974). Reason: Direct F-actin co-sedimentation supports the more specific term actin filament binding (GO:0051015). MGI already transfers GO:0051015 from this paper to mouse Eps8l2 by ISO, so the refinement matches existing curator practice. Proposed replacements: actin filament binding Supporting Evidence: PMID:14565974 Consistent with the immunoprecitation results, eps8, eps8L1, and L2, but not eps8L3 could directly associate to F-actin PMID:14565974 Similarly to eps8, eps8L1 and eps8L2, but not eps8L3 coprecipitated with actin |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | ACCEPT | Summary: Anti-flag immunocomplexes of EPS8L2 co-expressed with ABI1 and SOS1 release GDP from Rac (Rac-GEF activity), and this depends on ABI1. The isolated EPS8L2 C-terminus binds native SOS1, as the EPS8 effector region does to activate SOS1. Reason: The contributes_to qualifier is correct: SOS1 is the catalytic subunit, and EPS8L2 contributes to the Rac-GEF activity of the EPS8L2-ABI1-SOS1 complex as the activating subunit. This is a core function directly assayed for the human protein. Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Of note, the presence of the Rac-GEF activity, in the immunocomplexes, was dependent on the simultaneous transfection with Abi1, as predicted PMID:14565974 Native Sos-1 could be recovered onto immobilized GST-C-terminal fragments of eps8, eps8L2, and eps8L1 |
| GO:0005515 protein binding | IPI PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | REMOVE | Summary: Flag-EPS8L2 co-immunoprecipitates endogenous ABI1 (PMID:14565974); ABI1 scaffolds the EPS8L2-SOS1 Rac-GEF complex. Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The functional meaning of the ABI1 interaction, assembly of a complex with Rac-GEF activity, is captured by the contributes_to guanyl-nucleotide exchange factor activity annotation from the same paper. Supporting Evidence: PMID:14565974 under conditions of triple transfection, all of the eps8 family members could be found in association with Abi1 and Sos-1 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with DMWD from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with KIF1B isoform 2 from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with WFS1 from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with NEFL from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with CTSD from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with GRN from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with SPRED1 from a neurodegenerative-disease interactome map (PMID:32814053). Reason: Generic protein binding (GO:0005515) carries no functional information; per the project protein-binding policy it is removed. Removal does not mean the reported interaction is false. The binary screen gives no information about what EPS8L2 does with this partner, and no follow-up links the interaction to an EPS8L2 function. |
| GO:0005737 cytoplasm | EXP PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | KEEP AS NON CORE | Summary: Cytoplasmic localization of transfected EPS8L2 in fibroblasts, where it co-distributes with EPS8 (PMID:14565974). Reason: Correct and as precise as this evidence allows for the diffuse pool. The functionally relevant locations, ruffle membrane and stereocilium tip, are captured by other rows. Supporting Evidence: PMID:14565974 they show a very similar intracellular distribution as witnessed by the large extent of colocalization between the two proteins by confocal analysis |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to cytoplasm, based on the same PMID:14565974 data. Reason: Consistent with the EXP row for the same term; not a core location. Supporting Evidence: PMID:14565974 they show a very similar intracellular distribution as witnessed by the large extent of colocalization between the two proteins by confocal analysis |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence localization to cytosol. Reason: Plausible for a soluble actin-regulatory adaptor that is recruited to F-actin-rich structures; non-core location. HPA images were not inspected here. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MODIFY | Summary: IBA plasma membrane (is_active_in) from PAINT node PTN000958212. Reason: EPS8L2 is not known to be an integral or constitutive plasma membrane protein; the experimental data place it at PDGF-induced ruffle membranes, a part of the plasma membrane. Ruffle membrane (GO:0032587), which the gene already carries by IDA and IBA, is the specific supported term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000958212 SUPPORTS TRANSFER Membrane association is via recruitment to ruffles; the general plasma membrane term is refined to ruffle membrane. UniProtKB:Q9H6S3 SUPPORTS TRANSFER EPS8L2's own experimental annotation from PMID:14565974 is among the descendant evidence for this node; expected, not circular. UniProtKB:Q8TE68 SUPPORTS TRANSFER EPS8L1 shares the ABI1/SOS1 Rac-GEF and F-actin-binding properties in the same study. Proposed replacements: ruffle membrane Supporting Evidence: PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, were found enriched in PDGF-induced, F-actin |
| GO:0007266 Rho protein signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: IBA Rho protein signal transduction from PAINT node PTN000958212. Reason: The EPS8L2-ABI1-SOS1 complex activates Rac. In current GO, Rho protein signal transduction (GO:0007266) is defined for GTPases of the Rho subfamily, and Rac protein signal transduction (GO:0016601) is a sibling, not a descendant (checked against OLS ancestors). The correct term is therefore the Rac one; this is a lateral correction. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000958212 SUPPORTS TRANSFER The donor biology (activation of SOS1 toward Rac) is sound and inherited; the Rho-subfamily term is a lateral mis-scoping of Rac signalling. UniProtKB:Q9H6S3 SUPPORTS TRANSFER EPS8L2's own experimental annotation from PMID:14565974 is among the descendant evidence for this node; expected, not circular. UniProtKB:Q8TE68 SUPPORTS TRANSFER EPS8L1 shares the ABI1/SOS1 Rac-GEF and F-actin-binding properties in the same study. Proposed replacements: Rac protein signal transduction Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, mediate RTK-dependent actin remodeling, most likely by entering into a RacGEF complex with Abi1 and Sos-1 |
| GO:0007266 Rho protein signal transduction | IDA PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | MODIFY | Summary: Assigned from PMID:14565974, which shows EPS8L2 complexes with Rac-GEF activity and rescue of growth-factor-induced, Rac-dependent ruffling. Reason: The EPS8L2-ABI1-SOS1 complex activates Rac. In current GO, Rho protein signal transduction (GO:0007266) is defined for GTPases of the Rho subfamily, and Rac protein signal transduction (GO:0016601) is a sibling, not a descendant (checked against OLS ancestors). The correct term is therefore the Rac one; this is a lateral correction. Proposed replacements: Rac protein signal transduction Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, mediate RTK-dependent actin remodeling, most likely by entering into a RacGEF complex with Abi1 and Sos-1 |
| GO:0007266 Rho protein signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning prediction of Rho protein signal transduction. Reason: The EPS8L2-ABI1-SOS1 complex activates Rac. In current GO, Rho protein signal transduction (GO:0007266) is defined for GTPases of the Rho subfamily, and Rac protein signal transduction (GO:0016601) is a sibling, not a descendant (checked against OLS ancestors). The correct term is therefore the Rac one; this is a lateral correction. Proposed replacements: Rac protein signal transduction Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, mediate RTK-dependent actin remodeling, most likely by entering into a RacGEF complex with Abi1 and Sos-1 |
| GO:0007605 sensory perception of sound | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Eps8l2. Mouse Eps8l2 (Q99K30, same PANTHER subfamily PTHR12287:SF20) knockouts have late-onset progressive hearing loss with hair-bundle deterioration, and human biallelic loss-of-function variants cause DFNB106 progressive hearing loss. Reason: Kept, but non-core. The ortholog transfer is evolutionarily sound (same SF20 subfamily). However, the evidence is necessity evidence at the organism level; the cellular role of EPS8L2 is in maintaining the actin core and staircase of hair-cell stereocilia, upstream of hearing. Normal MET currents in immature knockout hair cells show it is not part of the transduction machinery itself. Supporting Evidence: PMID:23918390 Eps8L2 null-mutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology PMID:26282398 We concluded that this frame-shift mutation, predicted to result either in a truncated inactive protein, or in no protein at all due to nonsense-mediated mRNA decay, is responsible for the progressive hearing loss of the two Algerian patients file:interpro/panther/PTHR12287/PTHR12287-entries.csv Eps8l2,729,PTHR12287:SF20 |
| GO:0007605 sensory perception of sound | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: UniProt ISS transfer from mouse Eps8l2. Mouse Eps8l2 (Q99K30, same PANTHER subfamily PTHR12287:SF20) knockouts have late-onset progressive hearing loss with hair-bundle deterioration, and human biallelic loss-of-function variants cause DFNB106 progressive hearing loss. Reason: Kept, but non-core. The ortholog transfer is evolutionarily sound (same SF20 subfamily). However, the evidence is necessity evidence at the organism level; the cellular role of EPS8L2 is in maintaining the actin core and staircase of hair-cell stereocilia, upstream of hearing. Normal MET currents in immature knockout hair cells show it is not part of the transduction machinery itself. Supporting Evidence: PMID:23918390 Eps8L2 null-mutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology PMID:26282398 We concluded that this frame-shift mutation, predicted to result either in a truncated inactive protein, or in no protein at all due to nonsense-mediated mRNA decay, is responsible for the progressive hearing loss of the two Algerian patients file:interpro/panther/PTHR12287/PTHR12287-entries.csv EPS8L2,715,PTHR12287:SF20 |
| GO:0031982 vesicle | HDA PMID:19190083 Characterization of exosome-like vesicles released from huma... | KEEP AS NON CORE | Summary: Detected in exosome-like vesicles from human tracheobronchial epithelial cultures by mass spectrometry (PMID:19190083). Reason: High-throughput proteomic detection; plausible cargo of epithelial vesicles but no function there is known. Supporting Evidence: PMID:19190083 we demonstrate for the first time that exosome-like vesicles with antiviral properties are present in human tracheobronchial epithelial (HTBE) cell culture secretions |
| GO:0032420 stereocilium | IEA GO_REF:0000044 | MODIFY | Summary: UniProt SubCell mapping to stereocilium, by similarity to mouse Eps8l2. Reason: Stereocilium tip (GO:0032426) is part_of stereocilium, which is part_of stereocilium bundle (verified in OLS). Mouse Eps8l2, a same-subfamily (SF20) ortholog, is localized specifically at stereocilia tips by immunofluorescence, so the more specific tip term, which the gene already carries, is the supported refinement. Proposed replacements: stereocilium tip Supporting Evidence: PMID:23918390 is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells file:interpro/panther/PTHR12287/PTHR12287-entries.csv Eps8l2,729,PTHR12287:SF20 |
| GO:0032421 stereocilium bundle | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of stereocilium bundle from mouse Eps8l2. Reason: Stereocilium tip (GO:0032426) is part_of stereocilium, which is part_of stereocilium bundle (verified in OLS). Mouse Eps8l2, a same-subfamily (SF20) ortholog, is localized specifically at stereocilia tips by immunofluorescence, so the more specific tip term, which the gene already carries, is the supported refinement. Proposed replacements: stereocilium tip Supporting Evidence: PMID:23918390 is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells file:interpro/panther/PTHR12287/PTHR12287-entries.csv Eps8l2,729,PTHR12287:SF20 |
| GO:0032421 stereocilium bundle | ISS GO_REF:0000024 | MODIFY | Summary: UniProt ISS transfer of stereocilium bundle from mouse Eps8l2. Reason: Stereocilium tip (GO:0032426) is part_of stereocilium, which is part_of stereocilium bundle (verified in OLS). Mouse Eps8l2, a same-subfamily (SF20) ortholog, is localized specifically at stereocilia tips by immunofluorescence, so the more specific tip term, which the gene already carries, is the supported refinement. Proposed replacements: stereocilium tip Supporting Evidence: PMID:23918390 is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells file:interpro/panther/PTHR12287/PTHR12287-entries.csv Eps8l2,729,PTHR12287:SF20 |
| GO:0032426 stereocilium tip | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of stereocilium tip from mouse Eps8l2 (IDA, PMID:23918390). Reason: Mouse Eps8l2 (Q99K30) is in the same PANTHER subfamily (PTHR12287:SF20) as human EPS8L2, and its tip localization is independent of Eps8 and MyoXVa, so it is an intrinsic SF20 property rather than an Eps8 (SF21) trait. Not yet shown directly for the human protein. Supporting Evidence: PMID:23918390 is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells PMID:23918390 Eps8L2 labeling was high in the middle and shortest rows of fully grown stereocilia and was hardly detectable in the longest rows file:interpro/panther/PTHR12287/PTHR12287-entries.csv Eps8l2,729,PTHR12287:SF20 file:interpro/panther/PTHR12287/PTHR12287-entries.csv EPS8L2,715,PTHR12287:SF20 |
| GO:0032426 stereocilium tip | ISS GO_REF:0000024 | ACCEPT | Summary: UniProt ISS transfer of stereocilium tip from mouse Eps8l2 (IDA, PMID:23918390). Reason: Mouse Eps8l2 (Q99K30) is in the same PANTHER subfamily (PTHR12287:SF20) as human EPS8L2, and its tip localization is independent of Eps8 and MyoXVa, so it is an intrinsic SF20 property rather than an Eps8 (SF21) trait. Not yet shown directly for the human protein. Supporting Evidence: PMID:23918390 is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells PMID:23918390 Eps8L2 labeling was high in the middle and shortest rows of fully grown stereocilia and was hardly detectable in the longest rows file:interpro/panther/PTHR12287/PTHR12287-entries.csv Eps8l2,729,PTHR12287:SF20 file:interpro/panther/PTHR12287/PTHR12287-entries.csv EPS8L2,715,PTHR12287:SF20 |
| GO:0032587 ruffle membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA ruffle membrane from PAINT node PTN000264860 (donors mouse Eps8, human EPS8L1 and EPS8L2). Reason: Supported by direct evidence for human EPS8L2 recruitment to PDGF-induced ruffles; EPS8L2 in its own WITH/FROM reflects that experimental grounding. Supporting Evidence: PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, were found enriched in PDGF-induced, F-actin |
| GO:0032587 ruffle membrane | IDA PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | ACCEPT | Summary: Flag-EPS8L2 is enriched in PDGF-induced, F-actin-rich membrane ruffles in fibroblasts (PMID:14565974). Reason: Direct localization evidence for the human protein; the ruffle is where its Rac-GEF complex acts. Supporting Evidence: PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, were found enriched in PDGF-induced, F-actin |
| GO:0032587 ruffle membrane | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning prediction of ruffle membrane. Reason: Agrees with the experimental IDA and IBA rows for the same term. Supporting Evidence: PMID:14565974 Eps8L1 and eps8L2, similarly to eps8, were found enriched in PDGF-induced, F-actin |
| GO:0032991 protein-containing complex | IDA PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | KEEP AS NON CORE | Summary: EPS8L2 is part of an ABI1-dependent complex with ABI1 and SOS1 (PMID:14565974). Reason: Correct, but GO has no specific term for the EPS8-family/ABI1/SOS1 Rac-GEF complex, so the generic term is as precise as currently possible. The informative content is carried by the contributes_to GEF activity annotation. Supporting Evidence: PMID:14565974 under conditions of triple transfection, all of the eps8 family members could be found in association with Abi1 and Sos-1 file:human/EPS8L2/EPS8L2-uniprot.txt Interacts with ABI1. Part of a complex that contains SOS1 |
| GO:0035023 regulation of Rho protein signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: IBA regulation of Rho protein signal transduction from PAINT node PTN000958212. Reason: EPS8L2 activates the Rac-GEF activity of SOS1, i.e. it acts upstream to increase Rac signalling. Regulation of Rho protein signal transduction (GO:0035023) is for Rho-subfamily signalling; positive regulation of Rac protein signal transduction (GO:0035022) is not its descendant (checked in OLS) and is the correct, signed term. Lateral correction. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000958212 SUPPORTS TRANSFER The donor biology (activation of SOS1 toward Rac) is sound and inherited; the Rho-subfamily term is a lateral mis-scoping of Rac signalling. UniProtKB:Q9H6S3 SUPPORTS TRANSFER EPS8L2's own experimental annotation from PMID:14565974 is among the descendant evidence for this node; expected, not circular. UniProtKB:Q8TE68 SUPPORTS TRANSFER EPS8L1 shares the ABI1/SOS1 Rac-GEF and F-actin-binding properties in the same study. Proposed replacements: positive regulation of Rac protein signal transduction Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Of note, the presence of the Rac-GEF activity, in the immunocomplexes, was dependent on the simultaneous transfection with Abi1, as predicted |
| GO:0035023 regulation of Rho protein signal transduction | IDA PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | MODIFY | Summary: Assigned from PMID:14565974 (EPS8L2 complexes activate SOS1 toward Rac). Reason: EPS8L2 activates the Rac-GEF activity of SOS1, i.e. it acts upstream to increase Rac signalling. Regulation of Rho protein signal transduction (GO:0035023) is for Rho-subfamily signalling; positive regulation of Rac protein signal transduction (GO:0035022) is not its descendant (checked in OLS) and is the correct, signed term. Lateral correction. Proposed replacements: positive regulation of Rac protein signal transduction Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Of note, the presence of the Rac-GEF activity, in the immunocomplexes, was dependent on the simultaneous transfection with Abi1, as predicted |
| GO:0035023 regulation of Rho protein signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning prediction of regulation of Rho protein signal transduction. Reason: EPS8L2 activates the Rac-GEF activity of SOS1, i.e. it acts upstream to increase Rac signalling. Regulation of Rho protein signal transduction (GO:0035023) is for Rho-subfamily signalling; positive regulation of Rac protein signal transduction (GO:0035022) is not its descendant (checked in OLS) and is the correct, signed term. Lateral correction. Proposed replacements: positive regulation of Rac protein signal transduction Supporting Evidence: PMID:14565974 Eps8-, eps8L1-, and eps8L2-, but not eps8L3-containing immunocomplexes displayed RacGEF activity PMID:14565974 Of note, the presence of the Rac-GEF activity, in the immunocomplexes, was dependent on the simultaneous transfection with Abi1, as predicted |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: Identified by proximity biotinylation near the E-cadherin cytoplasmic tail (BioID) in an E-cadherin interactome screen (PMID:25468996). Reason: Proximity labelling shows EPS8L2 is near E-cadherin adhesions, not that it binds cadherin. No direct cadherin interaction has been shown, so the molecular function claim exceeds the evidence. Supporting Evidence: PMID:25468996 We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected in the human urinary exosome proteome (PMID:19056867). Reason: High-throughput proteomic detection in exosome preparations; consistent across several studies, but no known function there. Non-core. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Detected in human parotid saliva exosomes by MudPIT (PMID:19199708). Reason: High-throughput proteomic detection in exosome preparations; consistent across several studies, but no known function there. Non-core. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Detected in exosomes from expressed prostatic secretions in urine (PMID:23533145). Reason: High-throughput proteomic detection in exosome preparations; consistent across several studies, but no known function there. Non-core. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure |
| GO:1900029 positive regulation of ruffle assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IBA positive regulation of ruffle assembly from PAINT node PTN000264860. Reason: Human EPS8L2 restores PDGF-induced membrane ruffling in eps8-null fibroblasts, as efficiently as EPS8, and is itself recruited to ruffles where its Rac-GEF complex acts; it does part of the work (activating SOS1 toward Rac and binding F-actin) rather than being merely required. Supporting Evidence: PMID:14565974 Ectopic expression of eps8, eps8L1, or eps8L2, but not of eps8L3, restored ruffling formation, in response to growth factor stimulation, in eps8 null MEFs PMID:14565974 Notably, eps8L2 was as efficient as eps8 |
| GO:1900029 positive regulation of ruffle assembly | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning prediction of positive regulation of ruffle assembly. Reason: Agrees with the experimental IGI and IBA rows. Human EPS8L2 restores PDGF-induced membrane ruffling in eps8-null fibroblasts, as efficiently as EPS8, and is itself recruited to ruffles where its Rac-GEF complex acts; it does part of the work (activating SOS1 toward Rac and binding F-actin) rather than being merely required. Supporting Evidence: PMID:14565974 Ectopic expression of eps8, eps8L1, or eps8L2, but not of eps8L3, restored ruffling formation, in response to growth factor stimulation, in eps8 null MEFs |
| GO:1900029 positive regulation of ruffle assembly | IGI PMID:14565974 The eps8 family of proteins links growth factor stimulation ... | ACCEPT | Summary: Expression of human EPS8L2 in eps8-/- mouse embryo fibroblasts rescues growth-factor-induced ruffling (PMID:14565974). Reason: Human EPS8L2 restores PDGF-induced membrane ruffling in eps8-null fibroblasts, as efficiently as EPS8, and is itself recruited to ruffles where its Rac-GEF complex acts; it does part of the work (activating SOS1 toward Rac and binding F-actin) rather than being merely required. Supporting Evidence: PMID:14565974 Ectopic expression of eps8, eps8L1, or eps8L2, but not of eps8L3, restored ruffling formation, in response to growth factor stimulation, in eps8 null MEFs PMID:14565974 Notably, eps8L2 was as efficient as eps8 |
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Download this section (compressed HTML)Q: Should EPS8L2 carry stereocilium maintenance (GO:0120045)? Mouse knockouts show progressive loss of the staircase and stereocilium width, but MGI did not annotate this process from PMID:23918390, and it is unclear whether EPS8L2 performs a step (e.g. barbed-end capping or bundling at row-2 tips) or is only required.
Q: Does EPS8L2 cap actin filament barbed ends or bundle filaments, as EPS8 does, given that it lacks the IRSp53 binding that EPS8 needs for bundling?
Q: Is the EPS8L2-ABI1-SOS1 Rac-GEF complex assembled at stereocilia tips, or does EPS8L2 act there through other partners such as BAIAP2L2, TWF2 and CAPZB?
Experiment: Pyrene-actin barbed-end elongation and low-speed sedimentation bundling assays with purified full-length human EPS8L2 and its C-terminal effector region, compared with EPS8.
Experiment: Knock-in mice carrying DFNB106 variants or an effector-region actin-binding mutant, with row-specific stereocilia length and width measurements over time, to test whether F-actin binding is needed for bundle maintenance.
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